A major challenge in the field of metabolic physiology has been to understand the interorgan communication networks linking to glucose metabolism. One critical factor for this interorgan system is now known as hepatokines, identified from liver-derived proteins, and that play a pivotal role in regulating glucose metabolism and insulin sensitivity in skeletal muscle. ApoJ (apolipoprotienJ, also called clusterin) was not previously suspected to be involved in the regulation of glucose homeostasis and insulin signaling. Our preliminary data demonstrate that ApoJ may function as a hepatokine targeting insulin signaling and glucose metabolism in skeletal muscle, which could be mediated via the LRP1/2 (low-density lipoprotein receptor-related protein-1/2) signaling cascade. We thus hypothesize that the ApoJ ? LRP1/2 axis is a novel metabolic signaling network that is crucial for the maintenance of normal glucose homeostasis and insulin signaling and that this couples with the insulin receptor system. The overall objective of this proposal is to identify ApoJ as a novel hepatokine that controls muscle glucose homeostasis via LRP1/2 signaling coupled with the insulin receptor system. Specifically, Aim1 will establish the biological function of ApoJ as a new hepatokine in glucose metabolism. Aim2 will determine whether the ApoJ ? LRP1/2 signaling pathway is a key component of insulin action in skeletal muscle. Aim3 will elucidate the cellular mechanisms for the insulin-sensitizing effects of ApoJ. To accomplish these aims, we will use state-of-the-art technologies, including a conditional floxed ApoJ, LRP1 and LRP2 models as well as human subjects to clarify the metabolic function of the ApoJ ? LRP2 axis in the context of interorgan communication networks. These studies provide a unique opportunity to establish a new paradigm in which the ApoJ ? LRP2 signaling network is a key determinant of glucose homeostasis, and may offer a novel target for the treatment of obesity and diabetes.